Multi-scale systems biological models are increasingly developed to obtain comprehensive mechanistic insight into biological systems. The creation of such models is highly complex as modeling formalisms originating from various disciplines like e.g. biochemistry, physics and computer science are combined and semantically interweaved. As multi-scale models comprising even the organ scale continuously grow more complex, the demand for a solid tool base for the creation and simulation of such models will increase. Such tools should enable building and sharing re-usable modular model entities that can be semantically linked to a multi-scale model. Moreover, a clear separation of the model complexity and the technical complexity its realization and simulation is essential to target non-computer scientists as users. To this end, we developed the EPISIM platform for graphical multi-scale modeling and cell-based simulation of multicellular systems. We present the platform’s underling modeling concepts and multi-scaled tissue model architecture. The platforms applicability to different biological systems is demonstrated with exemplary models of human epidermal skin homeostasis and cell chemotaxis.

The EPISIM Platform consists of two ready-to-use, out-of-the-box software tools called EPISIM Modeller (graphical modeling system) and EPISIM Simulator (agent-based simulation environment). These tools allow the creation and simulation of multi-scale cell-based tissue models based on the developed EPISIM model architecture. Within the frame of this architecture multi-scale models are composed of modular models entities that are semantically integrated to tissue models by automatically generated model connector components (MCCs). The MCCs enable bidirectional access to model parameters and map the model’s different time scales.

Each EPISIM tissue model comprises a cell behavioral and a biomechanical model (CBM and BM). The BM covers all spatial and biophysical cell properties. Different BMs (lattice and off-lattice) are offered by the EPISIM simulation environment. These models can be dynamically linked to a CBM which is graphically modeled with process diagrams in the EPISIM modelling system. The graphical CBMs are automatically translated into executable code which is loaded by the EPISIM simulation environment conducting an agent-based tissue simulation. Moreover, automatic semantic integration of quantitative subcellular SBML models is offered. This allows the combination of discrete (deterministic and/or stochastic) and continuous models on cellular on subcellular scale. Such a model is linked to the tissue scale by the used BM. Reaction-Diffusion models of e.g. chemokines can be integrated in a multi-scale tissue model with extracellular diffusion fields.

We realized a multi-scaled simulation of human epidermal tissue homeostasis by integration Tysons cell cycle model into a graphical cell behavioral model of keratinocyte proliferation and differentiation. With another keratinocyte model we were able to reproduce a novel wound repair mechanism in silico. This mechanism was revealed by in vitro experiments with our standardized wound model based on full thickness tissue cultures. Finally, we were able to qualitatively reproduce the spatial T-cell arrangement around secretory cells with a chemotaxis model.